CN111297862B - 坏死性细胞凋亡抑制剂kw-2449及其作为药物的用途 - Google Patents
坏死性细胞凋亡抑制剂kw-2449及其作为药物的用途 Download PDFInfo
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Abstract
本发明属于医药技术领域，具体涉及坏死性细胞凋亡抑制剂KW‑2449及其作为药物的用途，特别是在制备坏死性细胞凋亡抑制剂及抗肿瘤、抗缺血性或顺铂诱导的急性肾损伤、抗阿尔茨海默病、抗缺血性心肌病、抗缺血性脑卒中、抗动脉粥样硬化、抗急性胰腺炎、抗儿童炎症性肠病、抗脓毒血症、抗沙门氏菌感染、抗李斯特菌感染、抗牛痘病毒感染等炎症和感染性相关疾病药物中的应用。
Description
技术领域
本发明属于医药技术领域，更具体地，本发明涉及坏死性细胞凋亡抑制剂KW-2449及其作为药物的用途。
背景技术
坏死性凋亡是最近发现的一种可调控的程序性细胞死亡方式，其在形态学上具有坏死的特征。研究表明，蛋白激酶RIPK1和RIPK3形成复合体并激活MLKL蛋白，MLKL多聚化后直接定位细胞膜上并导致细胞膜破裂是诱发程序性细胞坏死的关键机制。由于细胞内容物的释放，坏死性细胞凋亡会引起体内大量炎症细胞浸润从而诱发严重的炎症反应。坏死性细胞凋亡作为新的一类细胞程序性死亡方式，在缺血性损伤、急性肾损伤、神经退行性疾病、恶性肿瘤、病毒感染和免疫性疾病等多种疾病的病理生理过程中起重要作用。鉴定并发现坏死性细胞凋亡的小分子抑制剂对于坏死性细胞凋亡相关疾病的临床治疗具有十分重要的意义。
KW-2449的中文别名[4-[2-(1H-吲唑-3-基)乙烯基]苯基]-1-哌嗪基甲酮，化学式C20H20N40，强烈抑制Flt3(与慢性粒细胞白血病、骨髓增生异常有关)，对FGFR1，Bcr-Abl和Aurora A的抑制性适中，对PDGFRβ，IGF-1R，EGFR则无抑制性，目前未发现其直接作为RIPK1和RIPK3激酶的抑制剂发挥抗细胞坏死凋亡的药物用途报道。
发明内容
针对这种目前存在的问题，本发明提供坏死性细胞凋亡抑制剂KW-2449及其作为药物的用途，目的是提供一种新的抗坏死性细胞凋亡抑制剂，具体为化合物KW-2449及其药用盐，该化合物可作为RIPK1和RIPK3激酶的抑制剂而发挥抗细胞坏死性凋亡的活性。本发明的另一目的提供化合物KW-2449在制备抗肿瘤、抗急性肾损伤、抗阿尔茨海默病、抗缺血性心肌病、抗缺血性脑卒中、抗动脉粥样硬化、抗急性胰腺炎、抗儿童炎症性肠病、抗脓毒血症、抗沙门氏菌感染、抗李斯特菌感染、抗牛痘病毒感染等炎症和感染性相关疾病药物的新用途。
本发明通过对自有化合物库的筛选得到全新结构的坏死性细胞凋亡抑制剂。
本发明的具体技术方案如下：
作为本发明的第一方面，一种化合物KW-2449及其药用盐，结构如式(Ⅰ)所示，化合物为：[4-[2-(1H-吲唑-3-基)乙烯基]苯基]-1-哌嗪基甲酮或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备抗细胞坏死的药物；
本发明的化合物可按照常规方法制备为药用盐的形式，包括其有机酸盐及无机酸盐：无机酸包括但不限于盐酸、硫酸、磷酸、二磷酸、氢溴酸、硝酸等，有机酸包括但不限于乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸、草酸等。
在一个优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的药物作用靶点为RIPK1/RIPK3，通过抑制RIPK1/RIPK3激酶活性，从而抑制细胞坏死。
在本发明的另一方面，提供式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备RIPK1/RIPK3抑制剂药物。
在本发明的另一方面，提供式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备RIPK1/RIPK3激酶紊乱、过度激活或过度相互作用相关疾病的药物。
在一个优选例中，所述的RIPK1/RIPK3激酶紊乱、过度激活或过度相互作用相关疾病为炎症性、感染性、缺血性和退行性相关疾病或组织损伤。
在另一优选例中，所述的炎症性、感染性、缺血性和退行性相关疾病由RIPK1/RIPK3激酶介导，或由细胞坏死引发(通过抑制细胞坏死抑制炎症和感染性相关疾病)。
在另一优选例中，所述的炎症性、感染性、缺血性和退行性相关疾病包括但不限于：肿瘤、阿尔茨海默病、缺血性心肌病、缺血性脑卒中、动脉粥样硬化、急性胰腺炎、儿童炎症性肠病、抗脓毒血症、抗沙门氏菌感染、抗李斯特菌感染、抗牛痘病毒感染。
在另一优选例中，肿瘤包括食道、胃、肠、直肠、口腔、咽、喉、肺、结肠、乳腺、子宫、子宫内膜、卵巢、***、睾丸、膀胱、肾、肝、胰腺、骨、***、皮肤、眼、脑和中枢神经***等部位发生的癌症，以及甲状腺癌、白血病、霍金氏病、淋巴瘤和骨髓瘤。
在本发明的另一方面，提供一种抑制细胞坏死的方法，包括：以式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐处理细胞。
在一个优选例中，所述的抑制细胞坏死的方法是不以治疗疾病为目的的方法；如为体外细胞培养方法。
在一个优选例中，以式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐在体外处理细胞，显示具有非常优异的抗坏死性细胞凋亡作用。
在一个优选例中，以式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，用于制备抑制TNF-α引起的全身炎症综合征(SIRS)、乙酰氨基酚(APAP)诱导的肝毒性、顺铂诱导的急性肾损伤、缺血性肾损伤和乳腺癌转移的药物的用途。
在本发明的另一方面，提供一种预防、缓解或治疗炎症性、感染性、缺血性和退行性相关疾病的方法，包括：以式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐给予需要预防、缓解或治疗炎症和感染性相关疾病的对象。
本发明的其它方面由于本文的公开内容，对本领域的技术人员而言是显而易见的。
附图说明
图1是本发明实施例1利用自建药物库筛选抗坏死性凋亡的抑制剂结果图；
图2是本发明实施例2中KW-2449在不同浓度下对TSZ刺激后HT-29坏死性细胞凋亡的抑制作用图；
图3是本发明实施例3中KW-2449对不同细胞中坏死性凋亡的抑制活性作用图；
图4是本发明实施例4中KW-2449抑制RIPK1和RIPK3的磷酸化并阻止其相互作用图；
图5是本发明实施例5中KW-2449结合靶点确认图；
图6是本发明实施例7中KW-2449保护小鼠免受TNF-α诱导的全身免疫综合征(SIRS)图；
图7是本发明实施例8中KW-2449在体内保护小鼠免受对乙酰氨基酚(APAP)诱导的肝毒性图；
图8是本发明实施例9中坏死性细胞凋亡抑制剂KW-2449在体内保护由Cisplatin诱导的急性肾损伤图；
图9是本发明实施例10中坏死性细胞凋亡抑制剂KW-2449抑制小鼠乳腺癌肿瘤的肺转移图。
具体实施方式
以下对本发明的优选实例进行说明，应当理解，此处所描述的优选实施例仅用于说明解释本发明，并不用于限定本发明。
实施例1
从自有化合物库中筛选抗坏死性细胞凋亡抑制剂：
每个化合物用DMSO溶解成10mM母液备用，人结肠癌细胞HT-29铺于96孔板，每孔加入一种化合物10μM预刺激30分钟，然后用TNF-α，Smac mimetic和z-VAD-fmk(TSZ)诱导坏死性凋亡刺激6小时后，采用检测活细胞ATP含量法测定细胞生存率(使用Promega公司
Luminescent Cell Viability Assay试剂盒检测目录号：G7570)。
如图1所示，结果表明，在所筛选的120种化合物中大部分化合物都对经TSZ刺激所导致的坏死性细胞凋亡没有保护作用，只有KW-2449明显抑制了TSZ刺激所诱发的坏死性细胞凋亡。
实施例2
KW-2449具有的抗HT-29细胞坏死活性：
进一步考察KW-2449在不同浓度下对TNF-α诱导HT-29细胞发生坏死性凋亡的保护作用。我们发现KW-2449浓度依赖性的抑制由TSZ诱导的坏死性凋亡，其EC50为：0.95μM(图2A)。同时，在1-100μM的浓度下，KW-2449对HT-29细胞没有显著的毒性作用(图2B)。此外，KW-2449对TNF-α和Smac mimetic(TS)诱导的细胞凋亡无保护作用(图2C)。
实施例3
KW-2449对不同细胞的坏死性凋亡具有抑制活性的作用：
使用另一种人来源的细胞系(U937)和小鼠来源的细胞系(L929)，考察GNF-对TNF-α诱导下的不同细胞系坏死性凋亡的抑制活性。其中U937细胞用TNF-α，Smac mimetic和z-VAD-fmk(TSZ)刺激6小时，L929细胞系用TNF-α和z-VAD-fmk(TZ)刺激4小时。结果如图3所示，KW-2449浓度依赖性地抑制这两种细胞系坏死性凋亡的发生。
实施例4
KW-2449通过抑制RIPK1和RIPK3的磷酸化而抑制坏死性细胞凋亡：
HT-29细胞在KW-2449(1μM)处理30min后，用TSZ刺激不同时间点，考察RIPK1，RIPK3，MLKL及其磷酸化蛋白的表达，如图4A所示，KW-2449可以显著抑制RIPK1，RIPK3和MLKL的磷酸化，但是对RIPK1，RIPK3和MLKL蛋白本身的表达量没有影响。进一步，采用免疫共沉淀的方法(IP),考察了KW-2449能否抑制RIPK1和RIPK3在TSZ坏死激活后的相互作用，结果表明在TSZ处理4h之后，KW-2449可直接抑制细胞内RIPK1和RIPK3的相互作用(图4A和B)。
实施例5
坏死性细胞凋亡抑制剂KW-2449的靶点确认：
采用药物亲和响应靶标稳定性试验(DARTS)，依赖于靶蛋白对药物结合的蛋白酶敏感性的降低，以检测KW-2449与RIPK1/3激酶之间的潜在相互作用。如图5所示，在KW-2449的细胞的提取物中，在0.01％pronase蛋白酶的消化作用下，RIPK1和RIPK3蛋白都可以被保护，而在相同的样品中没有检测到MLKL被保护，提示KW-2449可与RIPK1和RIPK3相互作用。
实施例6
KW-2449抑制RIPK1和RIPK3的激酶活性：
进一步在体外通过配体激酶结合检测法(Ambit公司KinomeScanTM)检测KW-2449对RIPK1和RIPK3激酶和底物结合能力的抑制作用。KW-2449抑制了RIPK1和RIPK3激酶活性，其抑制作用Kd值为157nm。
实施例7
坏死性细胞凋亡抑制剂KW-2449在体内保护小鼠抵抗TNF诱导的全身免疫综合征(SIRS)：
验证KW-2449是否能够在体内保护RIP激酶驱动的炎症，首先在TNF-α诱导的SIRS模型中测试了其活性。在模型建立前3小时通过灌胃的方法给予小鼠KW-2449(10mg/kg)，然后通过静脉注射mTNF-α(400μg/kg)加上腹腔注射z-VAD-fmk(200μg)诱发小鼠发生SIRS。KW-2449能显著保护小鼠免于死亡(图6A)。此外，当这些小鼠在6小时检查时，通过KW-2449处理显著降低了IL-6在血清中的浓度水平(图6B)。因此，这些结果表明KW-2449在体内保护小鼠免受TNF-α诱导的SIRS。
实施例8
坏死性细胞凋亡抑制剂KW-2449在体内保护由乙酰氨基酚(APAP)诱导的肝损伤
以前的研究表明RIPK1是APAP诱导肝毒性所必需的，因此进一步研究KW-2449在这个模型中对组织损伤和炎症的影响。通过给小鼠注射对乙酰氨基酚(APAP,300mg/kg)诱发小鼠肝损伤。如图7所示，小鼠肝脏细胞明显坏死并且其血清中天冬氨酸转氨酶(AST)水平升高。发明人确定，对小鼠灌胃给予KW-2449(10mg/kg)能够显著降低小鼠的肝坏死(图7B)和血浆AST的水平(图7C)。总的来说，本实施例结果表明，KW-2449能够保护由乙酰氨基酚(APAP)诱导的肝损伤和体内炎症。
实施例9
坏死性细胞凋亡抑制剂KW-2449在体内保护由Cisplatin诱导的急性肾损伤：
前期已有文献报道坏死性细胞凋亡也参与了肿瘤化疗药物顺铂(Cisplatin)诱导的急性肾损伤。本实施例进一步检测坏死性细胞凋亡抑制剂KW-2449对顺铂诱导的急性肾损伤的保护作用。
首先对小鼠灌胃给予KW-2449(10mg/kg)，然后腹腔注射25mg/kg的顺铂,48小时后取出小鼠肾脏组织和血清检测其损失程度。其中，KW-2449每24小时灌胃一次。如图8A和B所示，顺铂诱发肾脏发生明显的病理性的坏死，而给予KW-2449明显抑制其诱发的肾脏坏死。同时，KW-2449明显抑制由于顺铂刺激造成的小鼠血清中肌酐(Creatinine)和尿素氮(BUN)的升高(图8C和D)。因此，坏死性细胞凋亡抑制剂KW-2449能够在体内保护由Cisplatin诱导的急性肾损伤。
实施例10
坏死性细胞凋亡抑制剂KW-2449能够抑制小鼠乳腺癌肿瘤的肺转移：
前期已有文献报道坏死性细胞凋亡促进了小鼠乳腺癌肿瘤的肺转移。本发明实施例进一步检测坏死性细胞凋亡抑制剂KW-2449对小鼠乳腺癌肿瘤的肺转移的抑制作用。我们对FVB/N小鼠乳腺中注射MVT-1乳腺癌细胞，4周后检测乳腺癌肺转移水平。其中，在乳腺癌细胞注射后2周对小鼠灌胃给药KW-2449(10mg/kg)，每2天给予一次。4周时检测小鼠乳腺癌肺转移水平。如图9A和B所示，KW-2449显著抑制了小鼠乳腺癌的肺转移。因此，坏死性细胞凋亡抑制剂KW-2449能够抑制小鼠乳腺癌肿瘤的肺转移。
以上实验结果表明，本发明的化合物KW-2449具有优异的抗细胞坏死活性，可作为RIPK1或RIPK3抑制剂，可抵抗TNF诱导的全身免疫综合征(SIRS)和对乙酰氨基酚(APAP)诱导的肝毒性，用于制备抗肿瘤、抗阿尔茨海默病、抗缺血性心肌病、抗缺血性脑卒中、抗动脉粥样硬化、抗急性胰腺炎、抗儿童炎症性肠病、抗脓毒血症、抗沙门氏菌感染、抗李斯特菌感染、抗牛痘病毒感染等炎症或感染性相关疾病的药物。
综上，因此本发明化合物及其盐类可以用于制备抗坏死性细胞凋亡抑制剂。
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (4)
1.式(I)所示化合物或它的药学上可接受的盐用于制备抑制TNF-α诱导的全身炎症综合征的药物的用途；
2.式(I)所示化合物或它的药学上可接受的盐用于制备抑制乙酰氨基酚诱导的肝损伤的药物的用途；
3.式(I)所示化合物或它的药学上可接受的盐用于制备抑制顺铂诱导的急性肾损伤的药物的用途；
4.式(I)所示化合物或它的药学上可接受的盐用于制备抑制乳腺癌肿瘤肺转移的药物的用途；
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|---|---|---|---|---|
| CN110179791A (zh) * | 2018-02-23 | 2019-08-30 | 第二军医大学第三附属医院 | 细胞坏死抑制剂tak-632及其作为药物的用途 |
Non-Patent Citations (3)
| Title |
|---|
| Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs;Sofie Martens等;《Trends in Pharmacological Sciences》;20200205;第41卷(第3期);第209-224页 * |
| Multi-kinase inhibitors, AURKs and cancer;Jonas Cicenas等;《Med Oncol》;20160401;第33卷(第43期);第1-11页 * |
| 抗细胞坏死小分子化合物的筛选及抗坏死活性的分子机理研究;刘磊;《万方数据知识服务平台》;20171129;第1-102页 * |
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| CN111297862A (zh) | 2020-06-19 |
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